Modulating Stress Granules via HDAC6 Inhibition: A Promising Strategy against Alzheimer's Disease

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Dysregulated cellular stress responses, particularly persistent stress granules (SGs), are increasingly linked to Alzheimer's disease (AD) pathogenesis.
• Stress granules are dynamic ribonucleoprotein assemblies that sequester translation complexes during cellular stress, normally resolving upon stress cessation.
• Aberrant SG formation under chronic stress may promote protein aggregation, neuroinflammation, and neurodegeneration in AD.

Purpose of the Study:

• To review the current understanding of HDAC6's role in regulating stress granule dynamics within the context of Alzheimer's disease.
• To identify key knowledge gaps concerning the mechanistic interplay between HDAC6, stress granules, and AD pathology.
• To discuss the therapeutic potential of targeting HDAC6 for modulating SG pathology and neuroinflammation in AD.

Main Methods:

• Literature review and synthesis of existing research on stress granules, HDAC6, and Alzheimer's disease.
• Analysis of studies investigating the molecular mechanisms linking HDAC6 activity to SG formation and resolution.
• Evaluation of preclinical and clinical data on HDAC6 inhibitors in models of neurodegenerative diseases.

Main Results:

• Evidence suggests HDAC6 plays a critical role in modulating stress granule dynamics, with its dysregulation potentially contributing to AD.
• Persistent SGs, influenced by HDAC6, may act as seeding platforms for pathological protein aggregates, exacerbating neuroinflammation.
• Heat shock proteins (HSPs) are implicated in the physiological resolution of SGs, a process potentially impaired in chronic stress conditions.

Conclusions:

• HDAC6 is a key regulator of stress granule dynamics relevant to Alzheimer's disease.
• Targeting HDAC6 offers a promising therapeutic strategy for mitigating SG-associated pathology and neuroinflammation in AD.
• Further research is needed to fully elucidate the precise mechanistic links and optimize HDAC6-targeted therapies for AD.